(a) Field of the Invention
This invention relates to novel peptides which are antagonist of the luteinizing hormone releasing hormone (LH-RH), which has the structure: p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2. More specifically, this invention relates to luteinizing hormone releasing factor (LH-RH) analogs, salts thereof, to processes and intermediates for peparing these analogs, and to pharmaceutical compositions and methods of use pertaining to these analogs.
The LH-RH analogs of this invention differ in structure from LH-RH by having the amino acid residues at positions 1, 2 and 6, and optionally at positions 3 and 10, replaced with other amino acid residues.
(b) Background of the Invention
For several years investigators have been searching for selective, potent antagonists of the LH-RH decapeptide. See the review article by D. H. Coy and A. V. Schally, Annals of Clinical Research, 10, 139 (1978). The high degree of interest in such antagonists is due to their usefulness in the endocrine field. A great number of compounds have been prepared as potential LH-RH antagonists but most of these compounds lack potency or are mixed agonist and antagonist of the LH-RH decapeptide. The most interesting antagonists to date have been compounds having a modified structure of LH-RH. For instance, [D-Phe.sup.2 ]-LH-RH, R. W. A. Rees et al., J. Med. Chem., 17, 1016 (1974); [D-Phe.sup.2, D-Phe.sup.6 ]-LH-RH, [D-Phe.sup.2, Phe.sup.3, D-Phe.sup.6 ]-LH-RH and [D-Phe.sup.2, D-Trp.sup.3, D-Phe.sup.6 ]-LH-RH, D. H. Coy et al., in "Peptides 1976", A. Loffet, Ed., Editions de l'Universite de Bruxelles, Brussells, Belgium, 1977, p 463; [D-p-F-Phe.sup.2 -D-Ala.sup.6 ]-LH-RH, C. W. Beattie et al., J. Med. Chem., 18, 1247 (1975) and [Ac-D-Phe.sup.1, D-Phe.sup.2, D-Trp.sup.3,6 ]-LH-RH, K. Channabasavaiah and J. M. Stewart, Biochem. Biophys. Res. Commun., 86, 1266 (1979).
The present invention provides pure LH-RH antagonists that are more potent than any of the LH-RH antagonists reported to date.